tbuckley/cabot-search huggingface dataset:
AGO-OVAR 2.29 (ENGOT-ov34): Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer (ROC).
Authors: Philipp Harter, Frederik Marmé, Patricia Pautier, Alexander Reuss, Kristina Lindemann, Christian Kurzeder, Els Van Nieuwenhuysen, Clemens Schmitt, Nadin Cron, Andres Redondo
Journal: Journal of Clinical Oncology (2022)

TPS5611 Background: Paclitaxel or pegylated liposomal doxorubicin in combination with bevacizumab constitutes a standard treatment option in patients with relapsed ovarian cancer who are not considered candidate for platinum, but responses are short-lived. Immune checkpoint inhibitors like atezolizumab as single agents have limited activity in ovarian cancer. There is a biologic rationale to combine checkpoint inhibitors with chemotherapy and bevacizumab, however, the role of such combination for the management of ovarian cancer is so far undefined. Because of the intimate relationship between angiogenesis and immunosuppression, it is expected that the inhibition of both pathways could lead to synergism and more durable clinical benefit. The addition of a chemotherapeutic agent is expected to lead to the release of tumor antigens and enhance the efficacy of immunotherapy in turn. Therefore, we aim to test the efficacy of atezolizumab in combination with non-platinum-based chemotherapy and bevacizumab vs the combination of a non-platinum-based chemotherapy and bevacizumab alone. Methods: AGO-OVAR 2.29 is a randomized (1:1), double blinded, phase III trial evaluating the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy (weekly paclitaxel or pegylated liposomal doxorubicin) compared with placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer with 1st or 2nd relapse within 6 months after completing platinum-based chemotherapy or 3rd relapse. A de novo tumor biopsy to determine the PD-L1 expression status prior to randomization for stratification is mandatory. Patients are treated with chemotherapy plus bevacizumab + atezolizumab/placebo until progression or unacceptable toxicity. Co-primary endpoints are overall survival and progression-free survival. It is planned to randomize approximately 664 patients. Safety interim analyses were performed after inclusion of 24 and an additional 60 and 120 patients who had completed at least one treatment cycle. As of 09 th February 2022, 461 patients have been randomized. Clinical trial information: NCT03353831.
Phase Ib/IIa study evaluating the safety and clinical activity of osimeritinib combined with anlotinib in EGFRm, treatment-naive advanced NSCLC patients (AUTOMAN).
Authors: Baohui Han, Bo Yan, Aiqin Gu, Tianqing Chu, Wei Zhang, Huiming Wang, Hua Zhong, Chunlei Shi, Xueyan Zhang
Journal: Journal of Clinical Oncology (2022)

e21140 Background: Limited data is known regarding osimertinib plus anlotinib as first line treatment in EGFRm advanced NSCLC patients. Earlier we have reported that osimertinib in combination with anlotinib was well tolerated. Here we further present the efficacy and safety profile of the combined therapy. Methods: In this phase Ib/IIa, open-label study, treatment-naïve patients with an activating EGFR mutation, advanced or metastatic lung adenocarcinoma were eligible. Patients with stable CNS metastases were allowed to enroll. Patients were treated with anlotinib at dose of 8mg, 10mg and 12mg, all patients received osimertinib 80mg. Primary endpoint was objective response rate (ORR) by investigator using RECIST v1.1. Secondary endpoints include disease control rate (DCR), depth of response, median progression free survival, overall survival rate at 12 months and safety profile. Data cut-off: Nov. 23 rd , 2021. Results: From November 2020 through June 2021, 25 patients were enrolled in the study and started treatment. Median age was 59 years (38-77years), 11 (44%) were female, 24 (96%) were ECOG PS 1. 24 (96%) patients were stage IV and 6 (24%) had CNS metastases. At DCO, 18 (72%) patients remained on treatment. Among 23 response evaluable patients, the overall ORR was 65.2% (95%CI 42.7,83.6), DCR was 95.7% (95%CI 78.0,99.9) and median depth of response was -40.7% (range, -70.6 to 49.7). Adverse events (AEs) were observed in 21 (84%) patients. The most common AEs were platelet count decreased (56.5%), thyroid-stimulating hormones increased (39.1%) and diarrhea (30.4%), no unexpected AEs occurred. Grade≥3 AEs and SAEs were experienced by 5 (20%) and two (8.0%) patients, respectively. Dose reduction occurred in 8 (32%) patients and all were related to anlotinib. There was no fatal AE event reported in this study. Conclusions: Osimertinib in combination with anlotinib as first-line treatment for naïve EGFRm advanced NSCLC patients showed encouraging antitumor activity with manageable safety profile. The study is ongoing and more results will be updated in the future. Clinical trial information: NCT04770688.
A pilot clinical study of VAL-413 (oral irinotecan HCl) in patients with recurrent pediatric solid tumors.
Authors: Dennis Brown, Jeffrey A. Bacha, James I. Geller, Patrick A. Thompson, Javier E. Oesterheld, Sarath Kanekal, Markos Leggas, Lorena Lopez, Neil Sankar, Noymi Yam, Lars M. Wagner
Journal: Journal of Clinical Oncology (2022)

TPS10063 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days, every 21 days has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001 ). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015 ). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet clinical need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. Methods: Eligibility: Up to 20 patients ≥ 1 year and ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 100mg/m2/day will be studied in combination with a fixed-dose of temozolomide using a standard 3 + 3 phase I design. In the event that the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; and comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed in all patients. This trial is ongoing (CT.gov: NCT04337177). Enrolment of the first dose level is ongoing, with no DLT observed to date. Clinical trial information: NCT04337177.
Adaptive response analysis of colorectal cancer cells to low-dose oxaliplatin as a tool to deciphering mechanisms of synergistic drug interaction.
Authors: Diego Tosi, Mathilde Robin, Marta Bini, Candice Marchive, Alexandre Djiane, Lisa Heron-Milhavet, Laurent Bréhélin, Céline Gongora
Journal: Journal of Clinical Oncology (2022)

3091 Background: Using an in vitro dose matrix approach, we previously showed in multiple colorectal cancer cell lines a striking cytotoxic synergism between oxaliplatin at very low concentrations and the ATR inhibitor VE-822. We confirmed this finding in vivo, and, surprisingly, in this setting the oxaliplatin-induced cell addiction to VE-822 persists over several days after oxaliplatin elimination. We tried to elucidate the molecular mechanism of the latter phenomenon. Methods: We evaluated by RNAseq the gene expression changes induced in vitro by low-dose oxaliplatin in the colorectal cancer cell line HCT-116 after 24 and 48 hours of treatment. In order to untangle the functional significance of the adaptive response to oxaliplatin, we performed on the RNAseq data an extensive gene set enrichment analysis (GSEA) using gene set from all Molecular Signature Database v7.4 collections with the exception of C7. For ontology-based gene set collections, we clusterized the enriched gene sets using the semantic similarity methodology in order to increase the readability of global functional response. Results: Extensive GSEA showed that after 24 hours of oxaliplatin treatment cancer cells upregulate several gene sets involved in aspecific responses to cellular stress or to various type of extracellular stimulations, including other organisms, oxygen-containing compounds, abiotic stimuli and hypoxia. In addition, several gene sets involved in proteolysis and autophagy are upregulated, suggesting a rewiring of cell machinery. After 48 hours of oxaliplatin treatment, we observed the activation of ribosome function, mitochondrial assembly and synthesis of aminoacids and ribonucleosides. Finally, a widespread negative enrichment of gene sets involved in DNA repair-related was detected both at 24 and at 48 hours, with a far greater negative enrichment at 48 hours, which suggest a commitment of cancer cell to a major limitation of DNA repairing capability lasting several days following a DNA damaging insult. Analysis of leading edge genes from the DNA repair gene sets showed a profound repression both at 24 and 48 hours of the transcripts of BRCA1, BRCA2, ATM, CHK1, WEE1, BARD1, BRIP1, NEHJ1, RAD51, XRCC2, CLSPN, GEN1, DNA2, EXO1, TOPBP1, POLE, RMI1. Interestingly, ATR mRNA was minimally repressed both at 24 and at 48 hours, which could explain the long-standing in vivo dependence of cancer cell to ATR after a brief oxaliplatin exposure. Conclusions: Extensive GSEA was able to elucidate the molecular mechanism underlying synergistic interaction between oxaliplatin and VE-822. The impact of profiling cancer cell adaptive responses by extensive GSEA should be further evaluated in the setting of rational development of drug combinations.
National cancer centers addressing climate change: An overview and analysis of organizations' sustainability plans.
Authors: Ashray Maniar, Katie Lichter, Marium Husain, Raina Kishan, Andrew Hantel
Journal: Journal of Clinical Oncology (2022)

e13623 Background: Climate change is one of the largest threats to human health and greenhouse gas (GHG) emissions are a substantial component of climate change. In the U.S., the healthcare industry accounts for an estimated 8.5% of GHG emissions, equating to the loss of 470,000 disability-adjusted life-years annually. Cancer care encapsulates a significant portion of hospital resources and climate change has disproportionate effects on cancer patients. Therefore, it is imperative and urgent that cancer centers actively engage in reducing healthcare related GHG emissions. In this systematic analysis and comprehensive review, we reviewed publicly accessible sustainability plans of National Cancer Institute (NCI)-designated Cancer Centers and their affiliated organizations to understand the involvement Cancer Centers have in their organization's sustainability efforts. Methods: We reviewed 64 NCI designated Cancer Centers, using the first 20 results of a Google search with terms: “Hospital X AND (climate action plan OR climate change OR sustainability plan OR carbon neutral)” and hospital homepages to identify publicly accessible sustainability plans for each organization. We reviewed the plans, performed a Google search/Cancer Center homepage search and messaged sustainability plan developers to identify involvement of the hospital and Cancer Center. We identified which hospitals assigned sustainability personnel. We performed a student’s t-test to assess for a correlation between incidence of lung cancer in a state and presence of a sustainability plan for that state’s Cancer Center. Data was collected by one reviewer, independently validated by a separate reviewer and differences were resolved by a joint data review. Results: Amongst the 65 Cancer Centers and organizations reviewed, 55 (36 university, 12 hospital, 7 joint) had publicly available sustainability plans. Of which, 31% (11/36) of university plans explicitly mentioned an affiliated hospital as part of the sustainability plan. Two Cancer Centers (3%) had independent sustainability plans and 7 (11%) centers mentioned sustainability on their homepage. 77% (23/30) of hospitals with sustainability plans identified sustainability personnel. We did not find an association between the existence of Cancer Center sustainability plan and that state’s lung cancer incidence rates (p = 0.932). Conclusions: In this review and analysis of NCI-designated Cancer Center sustainability plans, we found that while most centers’ affiliated organizations have publicly accessible sustainability plans, the majority (86%) of centers do not independently report on their sustainability efforts. These findings highlight a pressing need to increase engagement between Cancer Centers and their organizations regarding sustainability plans, and a need for greater transparency in publicizing sustainability plans.
Initiation of an eligibility screening protocol prior to tissue typing of potential stem cell donors resulted in substantial cost savings.
Authors: Luke St. John, Tara K. Gregory, Patricia Wagner, Sarah Meissner, Henning Schade, Scott Irvin Bearman, Richard A. Nash, Marcello Rotta, Jeffrey V. Matous, Alireza Eghtedar, Michael Timothy Tees, Michael B. Maris, Luke Mountjoy
Journal: Journal of Clinical Oncology (2022)

e19047 Background: Human Leukocyte Antigen (HLA) typing is a necessary but expensive process to identify suitable donors for allogeneic hematopoietic cell transplantation (HCT) for the treatment of bone marrow disorders and hematologic malignancies. The likelihood of a patient and sibling being fully HLA matched is 25%. An HLA-identical related donor remains the preferred source among HCT recipients due to superior outcomes when compared to unrelated, mismatched, haploidentical, or cord blood. Because of the high probability of finding an HLA matched donor among siblings, and the benefit of quick access to these donors, it had been standard procedure at our institute to test all siblings to identify potential matches. The estimated costs of HLA typing alone is approximately $300-$1000 and is contingent upon the lab utilized and resolution of typing. The costs of HLA typing, additional testing, and screening are significant to patients and health care systems. Methods: Our institution initiated a protocol to assess potential sibling donors prior to HLA typing as per the donor eligibility guidelines of the National Marrow Donor Program (NMDP). From 2018-2020 each sibling was given a questionnaire prior to HLA typing and screened for suitability. If a sibling was determined to be ineligible for donation based on the NMDP guidelines, HLA typing and work up for that sibling was not pursued. Results: Between 2018 and 2020 we identified 789 potential donors for HCT. All potential donors were sent eligibility questionnaires. Based on this screening, 568 potential donors were found to be eligible for donation whereas 221 were ineligible. HLA typing was pursued in all eligible donors. This resulted in and estimated cost savings of $66,000-$221,000 in HLA typing alone. This translated into a substantial health care cost savings for our institution as compared to our prior policy of typing all siblings. Conclusions: Identification and work up for potential HLA matched siblings is critical for identifying optimal donors for HCT. Our previous policy of universal sibling screening was found to be costly due to typing individuals who later were found to be ineligible to donate. We found that the initiation of a simple donor screening protocol that excluded ineligible sibling donors resulted in significant cost savings compared to our prior policy of HLA typing all potential sibling donors. Cost savings are a relevant consideration in all aspects of healthcare and this screening tool could be a practical component of the best practice guidelines for HLA matching and HCT.
Efficacy of an educational comic book for HPV vaccination information in Nigeria.
Authors: Mohana Roy, Atif Saleem, Ayah Said, Itoro E. Inoyo, Philip Garrity, Yetunde Bashorun, Tunji Anjorin, Paulette Ibeka, Danna Remen, Franklin W. Huang, Ami Siddharth Bhatt
Journal: Journal of Clinical Oncology (2022)

e18577 Background: In Nigeria, cervical cancer is the second most common cancer in part due to disparities in education, access to screening, and access to treatment. In Nigeria, the HPV vaccine is planned for introduction into the public sector but will not be mandated. Given the preventable nature of the disease and need for public awareness, we developed an easy-to-understand teaching tool, the Global Oncology (GO) Comic Book focused on both general cancer education and about cervical cancer and HPV vaccination. Methods: The GO Comic Book is set in modern-day Lagos, Nigeria and aims to dispel myths and misconceptions associated with cancer in general and cervical cancer in particular. After developing the comic book, we developed a teaching guide and a plan for a pilot distribution of the comic book to students in Nigeria. In late 2019, GO and programmatic partners including the Clinton Health Access Initiative (CHAI), Cancer Education and Advocacy Foundation of Nigeria (CEAFON) and Panaramic Comics (based in Lagos, Nigeria) successfully conducted a pilot distribution of the GO Comic Book to nearly 5,000 students representing 18 junior secondary schools in Lagos and Rivers states. The comic books were distributed as part of 12 school assemblies which featured interactive, live-readings of the comic book by students and Nigerian physician volunteers. Pre-/post-tests with 9 questions were administered to a subset of the students (N = 202) to assess change in knowledge before and after the educational assemblies and data was analyzed using descriptive statistics. Results: The response rate of the 202 administered surveys was 98% (N = 198) with 193 female (97.5%) and 5 male (2.5%) respondents. Participants were an average of 11.2 years of age. All multiple-choice-type assessment items showed shifts to better-informed responses following the educational intervention. The item with the highest positive-percent change as assessed in the post survey queried: “what types of virus can cause cervical cancer?” (pre-test = 25.2%, post-test = 68.2%). The table below shows the cervical cancer related questions that were asked and the proportion of correct answers. Conclusions: The GO comic book in conjunction with school assemblies, improved the knowledge regarding cervical cancer causes and risk factors in Nigerian school children. Findings highlight the lack of knowledge regarding cervical cancer among the young population eligible for HPV vaccination, and describe an effective educational strategy in this setting.[Table: see text]
Defining the optimal millimeter threshold for target lesion inclusion in the Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) based on outcome prediction.
Authors: Mishka Gidwani, Ken Chang, Jay Biren Patel, Albert Eusik Kim, Elizabeth R. Gerstner, Raymond Yi-kun Huang, Jayashree Kalpathy-Cramer
Journal: Journal of Clinical Oncology (2022)

e14003 Background: The Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) is the standard for therapeutic response assessment in brain metastases (BM) patients. The criteria relies on a human reader to annotate target (≥10 mm) and non-target (&lt;10mm) lesions of interest based on unidimensional measurement of lesion diameter on brain MRI. The change in the sum largest axial diameter of 5 target lesions (RANO-BM diameter) is then used to categorize intracranial response into 4 categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Methods: Automating the RANO-BM criteria (AUTO-RANO-BM) has enabled the rapid modulation of the threshold diameter required for inclusion of a brain metastasis as a target lesion. In this study, diameters below the RANO-BM 10mm recommendation were utilized when calculating the RANO-BM diameter. The ability of the RANO-BM diameter to predict overall survival for BM patients was then evaluated in a Cox Proportional Hazards model. In a cohort of 175 immunotherapy-treated BM patients, the optimal threshold for the RANO-BM diameter as measured by Concordance Index (C-Index) was 5mm, suggesting that the RANO-BM criteria should be amended.
Single-cell profiling of immune cells associated with response to neoadjuvant chemoimmunotherapy in IIIA non-small cell lung cancer (NSCLC).
Authors: Zhenzhen Hui, Jiali Zhang, Yulin Ren, Xiaoling Li, Wenwen Yu, Tao Wang, Liuqing Zheng, Shanshan Xiao, Yu-Long Chen, Feng Wei, Jian You, Xiubao Ren
Journal: Journal of Clinical Oncology (2022)

e20584 Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy (chemoimmunotherapy) in the neoadjuvant setting have achieved favorable clinical benefits in non-small cell lung cancer (NSCLC), but the underlying molecular mechanism has not been fully elucidated. Methods: To identify factors associated with the clinical outcome, single-cell RNA/TCR sequencing was performed using 10x Genomics on CD45 + immune cells isolated from tumor and multiple immune-relevant tissues and peripheral blood of four treatment-naïve and eight neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients (responders versus non-responders). Bioinformatics analysis was used to screen immune cell factors associated with therapy response in single-cell sequencing profiles, and results were verified at protein level by flow cytometry, multiplex fluorescent immunohistochemistry (mIHC) and ELISA. Results: A total of 186,477 immune cells from 48 samples were acquired after quality-control filtering. The synergistic increase of B cells and CD4 + T cells are associated with positive therapeutic response of neoadjuvant chemoimmunotherapy. B cell class switching to IgG1 and IgG3 plays a critical role in anti-tumor immune response in tumor lesion, and this process is driven by increased IL-21 protein secreted by infiltrated T follicular helper (Tfh) cells after neoadjuvant chemoimmunotherapy. Several critical events lead to the positive clinical outcome during neoadjuvant chemoimmunotherapy, including the diminished activated TNFRSF4 + regulatory T cells (Tregs), increased LAMP3 + dendritic cells (DCs), high pretreatment peripheral blood T-cell diversity, and the expansion of intratumoral CD4 + T clones and peripheral CD8 + T clones. A validation cohort of 26 treatment-naïve and 30 neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients verified these findings. Conclusions: Single-cell profiling of the immune response to neoadjuvant chemoimmunotherapy uncovered several critical factors of anti-tumor immune response and provided insight of potential novel predictive factors and therapeutic targets for improving the efficacy of treatment in NSCLC.